Treatment of lipodystrophy

ABSTRACT

An inhibitor of the rennin-angiotensin system is useful for the treatment or prevention of the lipodystrophy syndrome, e.g. in AIDS patients also receiving anti-retroviral therapy.

FIELD OF THE INVENTION

[0001] This invention relates to the treatment of lipodystrophy,especially in HIV-infected patients and in AIDS patients undergoinganti-retroviral therapy.

BACKGROUND OF THE INVENTION

[0002] With the introduction of highly active anti-retroviral therapy(HMRT) in 1996, the typical cachexia associated with AIDS has fallensharply, and the development of a new metabolic condition called “thelipodystrophy syndrome” has occurred. This new metabolic syndrome whichaffects HIV-infected patients receiving triple HAART was first describedonly recently, and is thought to be either an extension of the cachexiastate or an adverse effect of the HAART treatment.

[0003] The main clinical features of the lipodystrophy syndrome areperipheral fat loss, central fat accumulation and metabolicabnormalities which lead to lactoacidosis. The overall incidence ofthese physical abnormalities in recent reports and in abstractspresented at 1999 AIDS meetings is about 50% after 12-18 months oftherapy. The differences between these prevalence rates range from 18%to 83% due to confounding factors such as type and duration ofanti-retroviral therapy and the lack of an objective and validated casedefinition.

[0004] The metabolic features associated with lipodystrophy andprotease-inhibitor therapy include hypertriglyceridaemia,hypercholesterolaemia, insulin-resistance, type II diabetes mellitus andlactoacidosis. Dyslipidaemia at concentrations associated with increasedcardiovascular disease occurs has been reported in about 70% of HIVpatients receiving HAART. These metabolic abnormalities are moreprofound in those patients whose HAART regimen includes a proteaseinhibitor. More recently, peripheral fat loss has also been associatedwith low-grade lactic acidaemia liver dysfunction, but in the absence oflipid or glycaemic changes.

[0005] The metabolic changes of lipodystrophy may have serious clinicalconsequences. Several reports have described premature coronary-arterydisease in patients with few or no risk factors that were receivingprotease inhibitors. The increase in risk has been estimated fromavailable metabolic data to be 1.4 cardiac events per 1000patient-years.

[0006] It has been suggested that the lipodystrophy syndrome associatedwith protease inhibitors may be due to partial analogy between lipid andadipocyte regulatory proteins and the catalytic site of HIV-1 proteaseto which these protease inhibitors bind (Carr et al, Lancet 1998;351:1881-83). In vitro studies have shown that protease inhibitors caninhibit lipogenesis (Zhang et al, J. Clin. Endocrinol. Metab. 1999;84:4274-77, and Lenhard et al, Biochem Pharmacol 2000; 59:1063-68).

[0007] More recently, some features of this syndrome have been suggestedto represent mitochondrial toxicity of nucleotide analogue reversetranscriptase inhibitors (NRTIs). Peripheral lipoatrophy with fatredistribution in association with hyperlactaemia has been reported inpatients who received only NRTI)s. These changes also occur inHIV-uninfected patients with mitochondrial defects.

[0008] The results from a study investigating the underlying effect ofHIV-1 on metabolicand bodycomposition parameters concluded thatthemetabolic abnormalities of the HAART-associated lipodystrophy syndromemay be related to the HIV-1 infectious process or to factors associatedwith immunological dysfunction (Shikuma etal, AIDS 1999; 13:1359-65).Another study of HIV-positive subjects receiving HAART revealed thatlipodystrophy may result from the accumulation of T cells with impairedapoptosis, which are primed for TNF alpha synthesis (Ledru et al, Blood2000; 95(10):3191-8). Protease inhibitors themselves have also beenshown to impair T cell apoptosis (Sloand et al, Blood 1999;94(3):1021-7).

[0009] The renin-angiotensin system (RAS) and its components are knownand may be described as follows. Briefly, cells of the renaljuxta-glomerular apparatus produce the aspartyl protease renin whichacts on the alpha-2 globulin angiotensinogen (synthesised in the liver)to generate angiotensin I (AI). This non-pressor decapeptide isconverted to angiotensin II (ATII) by contact with thepeptidyldipeptidase angiotensin-converting enzyme (ACE). ATII stimulatesthe release of aldosterone, and is also a potent vasoconstrictor. Therenin-angiotensin system is therefore important in the maintenance andcontrol of blood pressure as well as the regulation of salt and watermetabolism. Renin, angiotensinogen and ACE have also been identified incardiovascular tissues including the heart and blood vessels, as hasmRNA for components of this system such as angiotensinogen. Receptorsfor angiotensin II have been found on vascular smooth muscle cells.Within tissues, the RAS may therefore have a local paracrine function,and the expression of the different components can be altered bypathophysiological stimuli such as sodium restriction. Kinetic studiessuggest that much of the circulating angiotensin I and 11 is derivedfrom the both renal and non-renal tissues.

[0010] There are many marketed or investigation-stage agents whichinhibit RAS activity, and many of them fall into two broad classes:inhibitors of angiotensin-converting enzyme, whose approved namesgenerally end in “pril” or in the case of active metabolites “prilat”,and antagonists at angiotensin receptors (more specifically, currently,the AT₁ receptor), whose approved names generally end in “sartan”. Alsopotentially of increasing importance may be a class of drugs known asneutral endopeptidase inhibitors, some of which will also have anACE-inhibitory effect or the potential to reduce RAS activity.

[0011] WO 99/20268 discloses that ACE inhibitors can enhance theperformance of those undergoing exercise, and suggests varioustherapeutic uses for such compounds, including the treatment ofcachexia.

SUMMARY OF THE INVENTION

[0012] The present invention is based on an understanding of howconventional anti-retroviral therapy may be associated with thelipodystrophy syndrome. In particular, it has been found that theadministration of a protease inhibitor (bestatin) is associated withincreased ACE activity in T-cells. While not wishing to be bound bytheory, this finding may help explain the mechanism by whichanti-retroviral therapy results in lipodystrophy. If anti-retroviraltherapy results in over-expression of ACE, the increased levels of ACEmay be a causative factor in lipodystrophy, due to its known effects onmetabolism, as discussed above. The mechanism by which inhibitors of therenin-angiotensin system operate, can be utilised to counteract certaindeleterious effects of anti-retroviral therapy.

[0013] Therefore, the present invention is based on the realisation thatinhibitors of the renin-angiotensin system may be used the therapy oflipodystrophy in AIDS patients undergoing anti-retroviral therapy.

[0014] According to a first aspect of the invention, an inhibitor of therenin-angiotensin system is used in the manufacture of a medicament forthe treatment or prevention of the lipodystrophy syndrome.

[0015] According to a second aspect of the invention, an inhibitor ofthe renin-angiotensin system is used in the manufacture of a medicamentfor the co-administration to a patient being administered a proteaseinhibitor and/or a reverse transcriptase inhibitor, for the treatment orprevention of a condition associated with a decrease in metabolicfunction.

[0016] The invention can provide an effective treatment for thelipodystrophy syndrome, and therefore offers an improvement inconventional AIDS therapy, with obvious benefit to the patient beingtreated.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Having described the various components of the RAS above, it willbe apparent that the system can be inhibited at various points. Inprinciple, it is expected that any sufficiently non-toxic compound whichis bioavailable and active to inhibit the RAS system at any suitablepoint can be used in the invention. This invention contemplates theadministration of all such agents (either singly or in combination witheach other and/or with other classes of pharmacological agents), andalso of pro-drugs which are converted in vivo to an active agent whichinhibits RAS activity. Note that RAS inhibition need not be totalinhibition; rather, sufficient inhibition to be beneficial in theinvention is all that is required. In practice, it is preferred at thepresent state of knowledge to use in the practice of the invention anyof the known RAS inhibitors which are either on the market or underinvestigation for their antihypertensive effects.

[0018] Many inhibitors of the renin-angiotensin system are licensed orunder investigation for use in humans in the United Kingdom and arecompounds whose use is preferred in the practice of the invention. Theyinclude the ACE-inhibitors Quinapril, Captopril, Lisinopril,Perindopril, Trandolapril, Enalapril, Moexipril, Fosinopril, Ramipril,Cilazapril, Imidapril, Spirapril, Temocapril, Benazepril, Alacepril,Ceronapril, Cilazapril, Delapril, Enalaprilat and Moveltipril. Suitableangiotensin II-inhibitors include Losartan, Valsartan, Irbesartan,Candesartan, Eprosartan, Tasosartan and Telmisartan.

[0019] The specific compounds listed may be useful in accordance withthe invention in their free form, for example as the free acid or baseas the case may be, and they may be useful as acid addition salts,esters, N-oxides or other derivatives as appropriate. The use ofsuitable pro-drugs (whether themselves active or inactive) and the useof active metabolites of RAS inhibitors are also within the scope of theinvention. For example, alacepril is a pro-drug for captopril, andenalaprilat is an active metabolite of enalapril.

[0020] Although ACE inhibitors and angiotensin II-receptor antagonistsare presently the most widely developed classes of drugs suitable foruse in the present invention, the invention is by no means limited totheir use.

[0021] ACE inhibitors may work through both a reduction in ATIIformation and through a reduction in kinin metabolism. Other agents mayalso inhibit kinin degradation, and as such have similarly beneficialeffects. These classes of drugs include inhibitors of neutralendopeptidases, some of which also of ACE-inhibitory properties. Theinvention thus contemplates the use of all kininase-inhibitors and kininreceptor antagonists (such as bradykinin).

[0022] The compounds for use in the invention are preferably lipophilic.However, the invention contemplates the use of compounds which areessentially non-lipophilic, or only moderately lipophilic, but whichhave been rendered more lipophilic either chemically, such as byappropriate derivatisation, or physically, such as by formulation withlipophilic carriers or delivery systems.

[0023] Administration of the active agent may be by any suitable route.As is conventional for ACE inhibitors at least, oral administration maybe preferred, especially for the purposes of achieving a prophylactic orpreventative effect. In certain circumstances, especially when a moreimmediate effect is required, intravenous administration may bepreferred. Suitable formulations for intravenous administration will beevident to those skilled in the art.

[0024] The optimum frequency of dosage and duration of treatment mayalso be established experimentally and/or clinically. Again by way ofexample, oral imidapril may be given once daily for an appropriateperiod of time. Frequencies of dosage for other compounds useful in theinvention will vary, and will depend on, among other things, thepharmacokinetics of the compound in question.

[0025] In a preferred embodiment, the inhibitor is administered morethan once a day in order to avoid peak inhibition of plasma ACE activitywhilst maximising tissue concentration. Altematively, an oral,subcutaneous or intramuscular slow release formulation may be providedto achieve the same effect.

[0026] The preferred therapy is for patients being co-administeredanti-retroviral therapy. The patients are most likely therefore to beHIV-infected (without AIDS symptoms) or suffering from AIDS. Theanti-retroviral therapy may be protease inhibitors and/or nucleosideanalogue reverse transcriptase inhibitors. The anti-retroviral compoundsdo not need to be administered at the same time as the inhibitors of therenin-angiotensin system. It is sufficient that the patient has beenadministered the anti-retrovirals. It is also not necessary that thepatient is actually suffering from cachexia modified by lipodystrophy orthe lipodystrophy syndrome, as the intended therapy may have aprophylactic effect.

[0027] The following study is intended to illustrate the utility of theinvention.

[0028] In order to evaluate the invention, a multi-centre, double-blind,placebo-controlled, randomised, parallel group, study is conducted.Patients are evaluated at a screening visit for signs of lipodystrophyas assessed by a patient and investigator questionnaire. Subjectsconsidered eligible have a fasting blood sample taken for themeasurement of serum triglyceride and ACE genotyping. In addition, bloodsamples are drawn for glucose, NEFA and insulin measurements at 0 (afterat least an 8 hour fast), 15, 30, 60 and 120 mins after an oral glucoseload.

[0029] Patients are randomised into two groups: 25 patients receivethree times daily treatment with placebo, and 25 patients receive threetimes daily treatment with imidapril hydrochloride (6.66 mg dose).

[0030] Each patient is tested on seven more occasions during the study,at 1, 2, 3, 4, 8 and 12 weeks after the start of treatment, and againfor a safety evaluation between 7 and 14 days of the last visit.

[0031] At all post-baseline visits, a fasting blood sample is drawn forclinical chemistry and haematology. At week 12, glucose, NEFA andinsulin levels are again measured at 0 (after an 8 hour fast), 15, 30,60 and 120 mins after an oral glucose load.

[0032] At all visits except weeks 1 and 3, weight, lean body mass,percentage body fat, waist, hip, thigh and arm circumferences, andskinfold thickness are measured using bioimpedence and anthropomorphicmethods. Vital signs (blood pressure and heart rate) and compliance withthe study medication are measured at each visit. At weeks 8 and 12, thepatient and physician are required to complete another questionnaire. Atweek 12, another full body DEXA scan is taken (no later than five daysafter the end of treatment).

[0033] Patients who withdraw from the study prior to the week 12 visitcomplete all assessments in the week 12 visit. The withdrawal assessmenttakes place as soon as possible after stopping treatment but no morethan 7 days after withdrawal. All subjects have a safety evaluationconducted 1-2 weeks after discontinuation of study drug.

[0034] Since imidapril is an antihypertensive agent, dose-dependentdecreases in blood pressure may be observed. All patients receive 6.66mg of imidapril hydrochloride or matched placebo three times daily. Ifthe 6.66 mg dose level of imidapril hydrochloride or matched placebo isnottolerated, the dose may be decreased to 3.33 mg three times daily forthe duration of the study. If the 3.33 mg dose level of imidaprilhydrochloride or matched placebo is not tolerated, the patient iswithdrawn.

1. A method for the treatment or prevention of the lipodystrophysyndrome wherein said method comprises administering, to a patient inneed of such treatment or prevention, an effective amount of aninhibitor of the rennin-angiotensin system.
 2. The method according toclaim 1, wherein the lipodystrophy syndrome is in a patient undergoinganti-retroviral therapy.
 3. The method according to claim 2, wherein theanti-retroviral therapy is the administration of a protease inhibitorand/or a reverse transcriptase inhibitor.
 4. The method according toclaim 1, wherein the inhibitor is lipophilic.
 5. The method according toclaim 1, wherein the inhibitor of the rennin-angiotensin system is aninhibitor of angiotensin-converting enzyme (“ACE”).
 6. The methodaccording to claim 5, wherein the ACE inhibitor is selected from thegroup consisting of quinapril, captopril, lisinopril, perindopril,trandolapril, enalapil,meoxipril, fosinopril, ramipril, cilazapril,imidapril, spirapril, temocapril, benazepril, alaceptril, ceronapil,cilazapril, delapril, enalaprilat, fosinopril and moveltpril.
 7. Themethod according to claim 6, wherein the ACE inhibitor is imidapril. 8.The method according to claim 1, wherein the inhibitor of therennin-angiotensin receptor antagonist.
 9. The method according to claim8, wherein the angiotensin receptor antagonists is an angiotenisin IIreceptor antagonist.